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Allergen-specific IgG antibodies signaling via FcRIIb promote food tolerance

Burton, OT;Tamayo, JM;Stranks, AJ;Koleoglou, KJ;Oettgen, HC;

Food-allergic subjects produce high-titer IgE antibodies that bind to mast cells via FcRI and trigger immediate hypersensitivity reactions upon antigen encounter. Food-specific IgG antibodies arise in the setting of naturally resolving food allergy and accompany the acquisition of food allergen unresponsiveness in oral immunotherapy (OIT). In this study, we sought to delineate the effects of IgG and its inhibitory Fc receptor, FcRIIb, on both de novo allergen sensitization in nave animals and on established immune responses in the setting of pre-existing food allergy. Allergen-specific IgG was administered to mice undergoing sensitization and desensitization to the model food allergen, ovalbumin (OVA). Cellular and molecular mechanisms were interrogated using mast cell- and FcRIIb-deficient mice. The requirement for FcRII in IgG-mediated inhibition of human mast cells was investigated using a neutralizing antibody. Administration of specific IgG to food allergy-prone IL4raF709 mice during initial food exposure prevented the development of IgE antibodies, T helper (Th) 2 responses, and anaphylactic responses upon challenge. When given as an adjunct to oral desensitization in mice with established IgE-mediated hypersensitivity, IgG facilitated tolerance restoration, favoring the expansion of Foxp3(+) regulatory T cells (Treg) along with suppression of existing Th2 and IgE responses. IgG and FcRIIb suppresses the adaptive allergic responses via effects on mast cell function. These findings suggest that allergen-specific IgG antibodies can act to induce and sustain immunological tolerance to foods.